A synthetic ophthalmic graft patch

ABSTRACT

The present invention provides synthetic ophthalmic graft patches, including devices comprising them, and uses thereof in ophthalmic tissue replacement therapies and ophthalmic tissue reconstruction/regeneration therapies.

BACKGROUND OF THE INVENTION

It is estimated that 285 million people worldwide are visually impaired,of whom 39 million are blind. Corneal opacities and trachoma alone areestimated to account for 4% and 3% of world blindness, respectively,ranking corneal blindness behind only cataract (51%) and glaucoma (8%).Nearly 185,000 corneal transplants are performed each year in over 115different countries, with nearly 80,000 performed in the US alone. Ofthe corneal grafts used worldwide, 87% are procured from donors withinthe same country, while 27 countries (1.2% of corneal transplants) relysolely on imported corneas to supply their need for corneal allografts.Limited access to viable graft tissue remains a challenge in many partsof the world, leaving over half of the world's population without accessto corneal transplantation services.

Scleral thinning is a well-reported complication following pterygiumexcision, glaucoma related surgery, retinal detachment repair, systemicdiseases such as vasculitis, high myopia, or trauma. In some cases, itresults in staphyloma formation, scleral perforation, and uvealexposure. Reinforcement of thin or perforated sclera is necessary,especially when the choroid is exposed to prevent prolapse of ocularcontents and secondary infection. Various types of grafts have been usedin this situation, but none has been uniformly accepted. Scleral graftsare typically available from donor eyes. Failure of scleral grafts hasbeen reported owing to lack of vascularization with resultant necrosis,sloughing and/or gradual degradation.

Eye banks are institutions responsible for collecting, processing, anddistributing donated ocular tissue for transplantation, helping tomitigate this disparity between harvested ocular tissue supply anddemand.

Since the grafts are derived from donors there are different potentialadverse events associated with corneal allograft transplantationincluding: infectious disease and serology (such as HIV), viralhepatitis, syphilis, endophthalmitis, sepsis, noninfectious systemicdisease transmission, malignancy, prion disease and so forth.

Due to infectious and communicable diseases, increased regulation, eyebanks cannot provide the increasing need and challenge of safe,high-quality, and timely tissue for any type of ophthalmictransplantation.

SUMMARY OF THE INVENTION

The present invention provides a synthetic ophthalmic graft patch havinga porous polymeric structure with pores of less than 5 microns. Theinvention further provides a synthetic ophthalmic graft patch having aporous polymeric structure with pores of between 5 and 20 micros.

When referring to a “synthetic ophthalmic graft patch”, it should beunderstood to encompass any type of synthetic artificial tissuesubstitute designated to be used to replace or complement any part ofthe eyeball and/or orbital anatomy. For example, said synthetic graftpatch of the invention, may be used in ophthalmic implantation ortransplantation procedures. In some examples said synthetic graft patchof the invention may be used to replace a diseased tissue of any part ofthe eyeball and/or orbit of a subject in need thereof. In other examplessaid synthetic graft patch of the invention may be used to complement orbe added to an implantable device used in an ophthalmic procedure.

It is to be understood that a synthetic ophthalmic graft patch of theinvention can be in any shape or form suitable for the procedure to beperformed and for the part of the anatomical eye part that is beingtreated. In some embodiments, the shape of a synthetic ophthalmic graftpatch of the invention is concaved. In other embodiments, the shape of asynthetic ophthalmic graft patch of the invention is convexed. In someembodiments, the shape of a synthetic ophthalmic graft patch of theinvention is in the form of a tube. In some embodiments, the shape of asynthetic ophthalmic graft patch of the invention is in the form of atleast part of the sclera of a patient. In some embodiments, the shape ofa synthetic ophthalmic graft patch of the invention is in the form of atleast part of the conjunctiva of a patient. In some embodiments, theshape of a synthetic ophthalmic graft patch of the invention is in theform of at least part of the cornea of a patient. In some embodiments,the shape of a synthetic ophthalmic graft patch of the invention is inthe form of at least a part of the eyelid, optionally with the tarsus,of a patient. In some embodiments, the shape of a synthetic ophthalmicgraft patch of the invention is in the form of at least a part of thelacrimal tube of a patient. In some embodiments, the shape of asynthetic ophthalmic graft patch of the invention is in the form of atleast a part of the tenon of a patient.

Said synthetic graft patch of the invention is defined to have a porouspolymeric structure with pores of less than 5 microns. In otherembodiments said pores have a size of between 0.1 to 5 microns. In otherembodiments said pores have a size of between 0.1 to 4 microns. In otherembodiments said pores have a size of between 0.1 to 3 microns. In otherembodiments said pores have a size of between 0.1 to 2 microns. In otherembodiments said pores have a size of between 0.1 to 1 microns. In otherembodiments, said pored have a size of 0.1, 0.2, 0.3, 0.5\4, 0.5, 0.6,0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5 microns.

In some embodiments, said pores have a size of between 5 to 20 microns.In some embodiments, said pores have a size of between 5 to 10 microns.In some embodiments, said pores have a size of between 5 to 15 microns.In some embodiments, said pores have a size of between 5 to 7 microns.In some embodiments, said pores have a size of 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20 microns.

In some embodiments, said synthetic ophthalmic graft patch of theinvention is a monolayered patch (i.e. it is constructed of a singlelayer of said porous polymeric structure). In other embodiments, saidsynthetic ophthalmic graft patch of the invention is a multi-layeredpatch (i.e. it is constructed of at least two layers of said porouspolymeric structure, which may be the same or different).

In some embodiments, said synthetic ophthalmic graft patch of theinvention is a biocompatible patch (i.e. the graft patch of theinvention is suitable to maintain long and/or short-term functionalitycompatible with the ophthalmic tissues it is replacing orcomplementing).

In other embodiments, said synthetic ophthalmic graft patch of theinvention is a biodegradable patch (i.e. said graft patch of theinvention disintegrates after a predetermined time period).

In some embodiments, said synthetic ophthalmic graft patch of theinvention has a thickness of at least 50 microns. In other embodiments,said synthetic ophthalmic graft patch of the invention has a thicknessof between about 50 to about 250 micrometers. In other embodiments, saidgraft patch thickness is about 50, 60, 70, 80, 90, 100, 110, 120, 130,140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 microns Inother embodiments said ophthalmic graft patch has a thickness of atleast 250 microns. In other embodiments, said graft patch thickness isbetween about 250 to about 2500 microns. In other embodiments, saidgraft patch thickness is about 250, 300, 350, 400, 450, 500, 550, 600,650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500,1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500 microns.

In other embodiments, said porous polymeric structure comprises at leastone polymer. In other embodiments, said porous polymeric structurecomprises at least two different polymers (difference may be related toany property including chemical properties (including but not limited totype of compounds, monomers, oligomers, stereochemistry and so forth),physical properties (including but not limited to length, pore size,flexibility, hydrophilicity, magnetic properties), biological properties(including but not limited to biocompatibility, biodegradability and soforth) of the polymers and any combination of properties thereof).

In further embodiments, said porous polymeric structure comprisesnanofibers.

In other embodiments, said porous polymeric structure comprises at leastone porous electrospun polymer.

In further embodiments, said porous polymeric structure comprises atleast one polymer selected from poly(DTE carbonate) polycaprolactone(PCL), polylactic acid (PLA), poly-L-lactic acid (PLLA),Poly(DL-lactide-co-caprolactone, Poly(ethylene-co-vinyl acetate) vinylacetate, Poly(methyl methacrylate), Poly(propylene carbonate),Poly(vinylidene fluoride), Polyacrylonitrile, Polycaprolactone,Polycarbomethylsilane, Polylactic acid, Polystyrene,Polyvinylpyrrolidone, poly vinyl alcohol (PVA), polyethylene oxide(PEO), polyurethane, polyvinyl chloride (PVC), hyaluronic acid (HA),chitosan, alginate, polyhydroxybuyrate and its copolymers, Nylon 11,Cellulose acetate, hydroxyappetite, poly(3-hydroxybutyricacid-co-3-hydroxyvaleric acid), poly(DL-lactide), polycaprolactone, andpoly(L-lactide) or any combination thereof.

Electrospun fibers are typically several orders in magnitude smallerthan those produced using conventional spinning techniques. Byoptimizing parameters such as: i) the intrinsic properties of thesolution including the polarity and surface tension of the solvent, themolecular weight and conformation of the polymer chain, and theviscosity, elasticity, and electrical conductivity of the solution; andii) the operational conditions such as the strength of electric field,the distance between spinneret and collector, and the feeding rate ofthe solution, electrospinning is capable of generating fibers as thin astens of nanometers in diameter. Additional parameters that affect theproperties of electrospun fiber include the molecular weight,molecular-weight distribution and structure (branched, linear etc.) ofthe polymer, solution properties (viscosity, conductivity and surfacetension), electric potential, flow rate and concentration, distancebetween the capillary and collection screen, ambient parameters(temperature, humidity and air velocity in the chamber), motion oftarget screen (collector) and so forth. Fabrication of highly porousfibers may be achieved by electrospinning the jet directly into acryogenic liquid. Well-defined pores developed on the surface of eachfiber as a result of temperature-induced phase separation between thepolymer and the solvent and the evaporation of solvent under afreeze-drying condition.

Several approaches have been developed to organize electrospun fibersinto aligned arrays. For example, electrospun fibers can be aligned intoa uniaxial array by replacing the single-piece collector with a pair ofconductive substrates separated by a void gap. In this case, thenanofibers tend to be stretched across the gap oriented perpendicular tothe edges of the electrodes. It was also shown that the pairedelectrodes could be patterned on an insulating substrate such as quartzor polystyrene so the uniaxially aligned fibers could be stackedlayer-by-layer into a 3D lattice. By controlling the electrode patternand/or the sequence for applying high voltage, it is also possible togenerate more complex architectures consisting of well-alignednanofibers.

Electrospun nanofibers could also be directly deposited on variousobjects to obtain nanofiber-based constructs with well-defined andcontrollable shapes. In addition, one can manually process membranes ofaligned or randomly oriented nanofibers into various types of constructsafter electrospinning: for example, fabrication of a tube by rolling upa fibrous membrane or the preparation of discs with controllablediameters by punching a fibrous membrane.

The present invention relates to any eletrospinning technique known inthe art, which includes Electrospinning, J. Stanger, N. Tucker, and M.Staiger, I-Smithers Rapra publishing (UK), An Introduction toElectrospinning and Nanofibers, S. Ramakrishna , K. Fujihara, W-E Teo,World Scientific Publishing Co. Pte Ltd (June 2005), Electrospinning ofmicro- and nanofibers: fundamentals and applications in separation andfiltration processes, Y. Fillatov, A. Budyka, and V. Kirichenko (Trans.D. Letterman), Begell House Inc., New York, USA, 2007, which are allincorporated herein by reference in their entirety.

Suitable electrospinning techniques are disclosed, e.g., inInternational Patent Application, Publication Nos. WO 2002/049535, WO2002/049536, WO 2002/049536, WO 2002/049678, WO 2002/074189, WO2002/074190, WO 2002/074191, WO 2005/032400 and WO 2005/065578, thecontents of which are hereby incorporated by reference. It is to beunderstood that although the according to the presently preferredembodiment of the invention is described with a particular emphasis tothe electrospinning technique, it is not intended to limit the scope ofthe invention to the electrospinning technique. Representative examplesof other spinning techniques suitable for the present embodimentsinclude, without limitation, a wet spinning technique, a dry spinningtechnique, a gel spinning technique, a dispersion spinning technique, areaction spinning technique or a tack spinning technique. Such and otherspinning techniques are known in the art and disclosed, e.g., in U.S.Pat. Nos., 3,737,508, 3,950,478, 3,996,321, 4,189,336, 4,402,900,4,421,707, 4,431,602, 4,557,732, 4,643,657, 4,804,511, 5,002,474,5,122,329, 5,387,387, 5,667,743, 6,248,273 and 6,252,031 the contents ofwhich are hereby incorporated by reference.

In some embodiments, said synthetic ophthalmic graft patch of theinvention further comprises at least one active agent.

In some embodiments, said at least one active agent is selected from aprotein, collagen, fibronectin, or TGF-beta 2, heparin, growth factors,antibodies, antimetabolites, chemotherapeutic agents, anti-inflammatoryagent, antibiotic agent, antimicrobial agent, and any combinationsthereof.

The invention further provides a synthetic ophthalmic graft patch asdisclosed herein and above being a tissue replacement patch.

The invention further provides a synthetic ophthalmic graft patch asdisclosed herein and above being a tissue supplement patch.

The invention further provides a synthetic ophthalmic graft patch asdisclosed herein and above being a tissue reconstruction/regenerationpatch.

The invention further provides a synthetic ophthalmic graft patch asdisclosed herein being at least a part of at least one of a sclera, aconjunctiva, cornea, an eyelid tarsus, lacrimal tube, a tenon of the eyeof a patient, and any combinations thereof.

The invention further provides a synthetic ophthalmic graft patch asdisclosed herein for use in ophthalmic tissue replacement procedures.The invention further provides a synthetic ophthalmic graft patch asdisclosed herein for use in ophthalmic tissue supplement procedures. Theinvention further provides a synthetic ophthalmic graft patch asdisclosed herein for use in ophthalmic tissuereconstruction/regeneration procedures. The invention further provides asynthetic ophthalmic graft patch as disclosed herein for use in.

The invention provides a synthetic ophthalmic graft patch of theinvention for use in ophthalmic tissue replacement therapy. Theinvention further provides a synthetic ophthalmic graft patch of theinvention for use in ophthalmic tissue reconstruction/regenerationtherapy.

In some embodiments, said ophthalmic tissue replacement and/orophthalmic tissue reconstruction and/or ophthalmic tissue regenerationtherapies are selected from eyelid tarsus supplement procedures,reinforcement of implants (for example for covering glaucoma tubeimplants or shunts in order to minimize the potential of tube erosion),correction of hypotony in an over-filtering bleb, scleral reinforcement(for example if there is an area of auto-filtration), repair of aneroded scleral buckle, anterior segment reconstruction, treatment ofocular tumors requiring radiotherapy, scleral reinforcement forscleromalacia, cryotherapy, scleral resection of ocular tumors and anycombinations thereof.

The invention further provides a synthetic ophthalmic graft patch asdisclosed herein for use in covering ophthalmic implants (for examplefor covering glaucoma tube implants or shunts in order to minimize thepotential of tube erosion).

The invention further provides a synthetic ophthalmic graft patch asdisclosed herein for use in correcting hypotony in an over-filteringbleb. The invention further provides a synthetic ophthalmic graft patchas disclosed herein for use in scleral reinforcement (for example ifthere is an area of auto-filtration). The invention further provides asynthetic ophthalmic graft patch as disclosed herein for use in therepair of an eroded scleral buckle. The invention further provides asynthetic ophthalmic graft patch as disclosed herein for use in anteriorsegment reconstruction. The invention further provides a syntheticophthalmic graft patch as disclosed herein for use in conjunction withtreatment of ocular tumors requiring radiotherapy. The invention furtherprovides a synthetic ophthalmic graft patch as disclosed herein for usein scleral reinforcement for scleromalacia. The invention furtherprovides a synthetic ophthalmic graft patch as disclosed herein for usein cryotherapy, or scleral resection of ocular tumors.

The invention further provides a device comprising at least onesynthetic ophthalmic graft patch as defined herein above and below.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIG. 1A, FIG. 1B and FIG. 1C show a scheme of a synthetic ophthalmicgraft patch of the invention wherein its capacity in eyelid tarsussupplement procedures.

FIG. 2A, FIG. 2B, FIG. 2C and FIG. 2D show an omega shaped syntheticophthalmic graft patch of the invention used to cover an implantabledevice, such as a tube glaucoma shunt.

It will be appreciated that for simplicity and clarity of illustration,elements shown in the figures have not necessarily been drawn to scale.For example, the dimensions of some of the elements may be exaggeratedrelative to other elements for clarity. Further, where consideredappropriate, reference numerals may be repeated among the figures toindicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

FIG. 1A. FIG. 1B and FIG. 1C shows the synthetic ophthalmic graft patchof the invention wherein its capacity in eyelid tarsus supplementprocedures. FIG. 1A-1C shows a synthetic ophthalmic graft patch of theinvention (101, 102 and 106) in the form of at least a part of theeyelid of a patient in need thereof, made of an electrospun porouspolymeric structure (103, 107 and 109). The synthetic ophthalmic graftpatch of the invention is shown in 102 and 106 wherein the anteriorelectro spun matrix (105) is peeled off (for visualization purposesonly), showing the underlying rigid, synthetic, artificial tarsus (104and 108).

FIG. 2A, FIG. 2B, FIG. 2C and FIG. 2D show an omega shaped syntheticophthalmic graft patch of the invention (201, 203 and in cross section202 and 206) made an electrospun porous polymeric structure (205) whichis formed to cover within its curved space (205, 207) an implantabledevice, such as a tube glaucoma shunt. Using such a synthetic ophthalmicgraft patch of the invention, allows the sunt to be implemented in placewithout the need of a donor graft tissue, having higher degree ofimplantation success. The omega shaped synthetic ophthalmic graft patchof the invention is placed in position using also the optional flatbottom part (204 and 208).

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

1-12. (canceled)
 13. A method of replacing and/or reconstructing and/orregenerating of ophthalmic tissue; said method comprising implanting asynthetic ophthalmic graft patch having a porous polymeric structurewith pores of less than 5 microns.
 14. A method of replacing and/orreconstructing and/or regenerating of ophthalmic tissue; said methodcomprising implanting a synthetic ophthalmic graft patch having a porouspolymeric structure with pores of between 5 to 20 microns.
 15. A methodaccording to claim 13, wherein said synthetic ophthalmic graft patch isa biocompatible patch.
 16. A method according to claim 13, wherein saidsynthetic ophthalmic graft patch is a biodegradable patch.
 17. A methodaccording to claim 13, wherein said synthetic ophthalmic graft patch hasa thickness of between 50 to 250 microns.
 18. A method according toclaim 13, wherein said synthetic ophthalmic graft patch has a thicknessof between 250 to 2500 microns.
 19. A method according to claim 13,wherein said porous polymeric structure comprises at least one polymer.20. A method according to claim 13, wherein said porous polymericstructure comprises nanofibers.
 21. A method according to claim 13,wherein said porous polymeric structure comprises at least one porouselectrospun polymer.
 22. A method according to claim 13, wherein saidporous polymeric structure comprises at least one polymer selected frompoly(DTE carbonate) polycaprolactone (PCL), polylactic acid (PLA),poly-L-lactic acid (PLLA), Poly(DL-lactide-co-caprolactone,Poly(ethylene-co-vinyl acetate) vinyl acetate, Poly(methylmethacrylate), Poly(propylene carbonate), Poly(vinylidene fluoride),Polyacrylonitrile, Polycaprolactone, Polycarbomethylsilane, Polylacticacid, Polystyrene, Polyvinylpyrrolidone, poly vinyl alcohol (PVA),polyethylene oxide (PEO), polyurethane, polyvinyl chloride (PVC),hyaluronic acid (HA), chitosan, alginate, polyhydroxybuyrate and itscopolymers, Nylon 11, Cellulose acetate, hydroxyappetite,poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid), poly(DL-lactide),polycaprolactone, and poly(L-lactide) or any combination thereof.
 23. Amethod according to claim 13, wherein said synthetic ophthalmic graftpatch further comprises at least one active agent.